The applicant describes a 5-year career development program leading to independent academic research in basic research as a molecular biologist under the mentorship of Prof. Matthew Warman, a leader in bone disease and skeletal development. The 2 goals of this program are: (1) to gain the foundational biological knowledge and skills to become an independent researcher in bone disease, for the career development half, and (2) to delineate the role of valosin containing protein (VCP) in Paget's disease of the bone which in turn can be used as a starting point to identify the muscle and neuronal disease pathways affected by mutations in VCP, for the research half. The candidate will have full access to the rich multi-disciplinary resources at Children's Hospital Boston and the Warman Laboratory for academic research growth. RESEARCH: I have published clinical and molecular findings in several families with the unusual combination of hereditary inclusion body myopathy, Paget disease of bone and frontotemporal dementia, now called IBMPFD (MIM 605382). I have recently identified the gene for IBMPFD as VCP. VCP is ubiquitous, essential, and highly abundant in cells. VCP is involved in an unusually wide variety of functions and is associated With distinct and crucial cell protein pathways, namely homotypic membrane fusion, postmitotic Golgi reassembly, and ubiquitin-dependent protein degradation. Given that the clinical manifestation of IBMPFD is very specific in the tissues affected, it seems likely that VCP has tissue and cell type specific functions which are as of yet unidentified. The primary focus of this application is to characterize the role of VCP in Paget's disease of the bone, via 2 Specific Aims: (1) Characterize the skeletal phenotype of the IBMPFD mouse. (2) In part 1 of this Aim, I will identify if VCP is itself a substrate for the autophagosome and if VCP is critical for the formation and activation of the autophagosome. In part 2, I will test the hypothesis that it is a disruption of the basal macroautophagy pathway that is the underlying molecular lesion that causes Paget disease of bone.